Retinal dystrophies, including inherited retinal dystrophies (IRDs), form a large group of genetically and phenotypically heterogeneous diseases that are characterised by progressive loss of photoreceptor cells and concomitant loss of vision. IRDs affect approximately 1 in 3000 people in Europe and the United States. To date about 200 genes and a further 50 loci associated with retinal dystrophy have been identified. The majority of these disorders are caused by loss-of-function mutations acquired by recessive or X-linked inheritance.
Substantial variation exists with respect to the onset, rate of vision loss, and the primary cell type affected. The most severe forms of inherited retinal degeneration are the various types of Leber congenital amaurosis (LCA), in which there is severe visual impairment from birth and often complete loss of vision during the first two decades. Although the primary cell type most commonly affected in retinal degeneration is the photoreceptor cell, defects in other cell types such as the retinal pigment epithelium (RPE) can lead to reduced photoreceptor function and their subsequent loss.
An example of an inherited retinal dystrophy owing to a defect in the RPE is a form of LCA caused by defects in the RPE-predominant iron-dependent retinoid isomerohydrolase RPE65, which accounts for between 6 and 16% of LCA cases. Its absence results in the disruption of the visual cycle leading to absent rod function and, consequently, to photoreceptor degeneration.
Several clinical and pre-clinical gene-replacement therapy studies have shown that subretinal delivery of adenoviral AAV2 vectors is safe, and can result in increased visual function (Bainbridge et al. 2008, Maguire et al. 2008, 2009, Hauswirth et al. 2008, Cideciyan et al 2008, 2009) and activity in the visual cortex (Ashtari et al. 2011).
However, in a previous investigation into gene-therapy replacement of RPE65 in the RPE (Bainbridge et al. 2008), the authors reported that though there were improvements to retinal sensitivity and visual-guided mobility in one patient upon treatment, there were no significant improvements in visual acuity and peripheral field vision. Additionally, there were no significant improvements in all measured parameters in the other treated patients. Improvements in electroretinographic responses have yet to be reported in any study. It has also been observed that treating RPE65−/− dogs at 30 months with AAV2/4 vector-mediated therapy did not rescue vision or retinal function (Le Meur et al. 2007).
Therefore, there is a need for improvements in gene-replacement therapies for retinal dystrophies, especially inherited retinal dystrophies, in particular for disorders of the retinal pigment epithelium (RPE) such as Leber congenital amaurosis.